Objective: To assess the efficacy and safety of ultra-low dose 0.005% estriol vaginal gel in women with breast cancer receiving nonsteroidal aromatase inhibitors (NSAIs) and experiencing treatment-related vulvovaginal symptoms and signs. Methods: Women with hormone receptor-positive early breast cancer receiving NSAIs were randomized to either estriol vaginal gel or placebo for 12 weeks. Vaginal maturation, vaginal pH, and total and individual scores of symptoms and signs of vulvovaginal atrophy were assessed at baseline and at weeks 3 and 12; sexual functioning was also evaluated using the Female Sexual Functioning Index (FSFI) questionnaire, as well as circulating estrogens, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Results: Sixty-one women with a mean age of 59 years were included: 50 received 0.005% estriol vaginal gel and 11 received placebo. Active treatment significantly improved maturation value and pH, vaginal dryness and global scores of symptoms and signs. Active treatment also increased the total FSFI score and all the FSFI domains, with the exception of pain. Small oscillations were observed in FSH and LH, which remained within the postmenopausal range. Estriol levels increased initially and normalized by week 12, and estradiol and estrone remained mostly undetectable throughout the study. Conclusions: Ultra-low dose 0.005% estriol vaginal gel showed efficacy in improving the symptoms and signs of vulvovaginal atrophy. These results, together with minimal oscillations in hormonal levels throughout the treatment, support the use of ultra-low dose 0.005% estriol vaginal gel as a treatment option for vulvovaginal atrophy in women with breast cancer receiving NSAIs with an indication for treatment with vaginal estrogens. Video Summary: http://links.lww.com/MENO/A531.

BACKGROUND: 0.005% Estriol vaginal gel is a new formulation for the local treatment of postmenopausal vaginal atrophy which delivers an ultra-low dose of estriol (50mcg) per application. A study is proposed with the hypothesis that 0.005% Estriol vaginal gel is an efficacious and safe option to treat moderate to severe symptoms of vaginal atrophy caused by AIs without producing significant decline in gonadotropins or increase in systemic estrogens. METHODS: 70 women with breast cancer receiving AIs and suffering from moderate to severe symptoms of vaginal atrophy were randomized to receive 1g of estriol gel or placebo gel (4:1) daily for 3 weeks and twice weekly up to 12 weeks. Preliminary data from an initial phase comprising 10 women treated for 3 weeks suggested that 0.005% Estriol vaginal gel did not have an influence on hypophyseal axis or estrogens. In the second study phase planned in 60 women, vaginal dryness and other symptoms and signs were analyzed with a 4-point severity scale (none, mild, moderate, severe) at baseline and at weeks 3 and 12. Estriol (E3), estradiol (E2) and estrone (E1) were analyzed by ultrasensitive LC-MS/MS assay (LOQ: 1pg/ml, 3pg/ml and 5pg/ml for E3, E2 and E1, respectively) at baseline and at weeks 1, 3, 8 and 12. FSH and LH were determined by Chemiluminiscency at the same timepoints and also at screening. Changes in vaginal parameters and hormonal levels were assessed. Adverse events were collected. RESULTS: 61 women aged 59.2 (7.1) from 5 sites in Spain and Karolinska University Hospital in Sweden comprised the ITT analysis. At baseline, all women but one were treated with anastrozole or letrozole. One-third complained from moderate and two-thirds from severe vaginal dryness. 50 received estriol and 11 placebo. Women that received estriol slightly increased E3 levels [median (Q25-Q75)] to 3.9 (0.5-12.1), 1.9 (0.5-6.8), 0.5 (0.5-6.0) and 0.5 (0.5-7.3) pg/ml at w1, w3, w8 and w12 respectively. In these women E2 and E1 remained below LOQ in all samples but one at w12. Variation of FSH between baseline and w12 was not different from the variation of FSH before treatment (p=0.11 Wilcoxon), while small oscillations were observed between baseline and w1 and baseline and w3 as compared to FSH variation before treatment (p<0.05 Friedman, Dunn's correction). A clinical superiority was observed at the end of treatment in women that received estriol in the improvement of their vaginal dryness,vaginal maturation value and score of vaginal signs vs those that received placebo ( p<0.01, p=0.01, p<0.01, respectively, Mann-Whitney-Wilcoxon). One serious adverse event emerged before the patient initiated treatment. CONCLUSIONS: These data confirm the efficacy of 0.005% Estriol vaginal gel in women with breast cancer suffering from bothersome vaginal symptoms, with a transitory negligible absorption of estriol in initial weeks and a non-significant variation of FSH after 12 weeks of treatment. These findings provide confidence for the safe use of 0.005% Estriol vaginal gel in women with breast cancer with an indication for vaginal symptoms improvement. Citation Format: Sánchez-Rovira P, Hirschberg AL, Gil-Gil M, Antolín-Novoa S, García-Estévez L, Bermejo de las Heras B, Presa-Lorite J, Sánchez-Vigil de la Villa I, Suárez-Almarza J, Nieto-Magro C. 0.005% estriol vaginal gel in hormone receptor-positive postmenopausal women with early stage breast cancer in treatment with aromatase inhibitors (AIs) in the adjuvant setting. A phase II prospective, randomized, double-blind placebo-controlled study - “the Blissafe study” [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-12-01.